Proteins, which often are sensitive to storage in liquids, are normally freeze-dried and reconstituted by the patient shortly before injection.
When preparing a syringe with a therapeutical amount of a protein for the patient, important criteria are:
Acceptable stability of the powder before reconstitution. The preparation should have at least as good quality as freeze-dried products on the market. The dried product should be able to be stored at room temperature, at least for a certain time.
No pain when given to patients, e.g. by using an isotonic solution and a small injection volume.
Acceptable reconstitution time.
A device for preparation of an injectable solution of substances sensitive to degradation is described in U.S. Pat. No. 4,968,299, and which is available under the trademark KabiPen.RTM. on the market. With KabiPen.RTM. the patient is provided with a device which is rather simple to handle. The device comprises a two-chamber ampoule Genomix.RTM. containing hGH (human Growth Hormone) as a lyophilized powder in one of the compartments and a reconstitution solution in the other. The patient reconstitutes the product before use. The reconstituted product is then stable for 3 weeks when stored at 2-8.degree. C. This device is a multiple-dose syringe.
There is also a one dose device on the market for growth hormone available under the trademark KabiQuick.RTM., which has an injection volume of 0.5 ml or more.
In the patent application WO 89/09614, of Genentech, a stabilized formulation of hGH comprising glycine, mannitol and a buffer is disclosed and in a preferred embodiment a non-ionic surfactant such as polysorbate 80 is added. Sodium-phosphate is suggested as buffer substance. The formulation has an increased stability in a lyophilized formulation and upon reconstitution. The final ratio of the ingredients is obtained by buffer exchange on a gel filtration column.
Nothing is mentioned about the volume injected to the patient, nor the amount of the protein.
In the patent application WO 91/18621 (GENENTECH) mannitol is generally mentioned as carrier for stability of GH and IGF.
The patent application WO 94/03198 (GENENTECH) discloses an aqueous formulation with GH+ buffer+ surfactant+ mannitol.
There has been a desire to find a one dose syringe, which has an injectable volume of less than 0.5 ml and a low amount of protein per dose and which can be produced by freeze-drying without production problems.
It was noticed that when a one-dose syringe with protein in a low amount in a small injection volume was produced, problems arise when the solution in the first chamber of the syringe is freeze-dried.
The matrix of the freeze-dried cake was non-coherent, and this resulted surprisingly in blow out. The cake burst in the chamber and the protein was thus lost. This is not acceptable, not only for production reason, but also for economical reasons when a medicament including an expensive protein is produced. A solution to this problem must therefore be found.
This problem does not occur when KabiQuick or other freeze-dried protein products are prepared. It was noticed that these products have a high amount of protein and amino acid. The problem arising for a low amount of protein per dose has now been solved by the present invention.